In primates, treatment with antiprogestins including RU 486 and ZK 137 316 will both block progesterone (P) action, and also inhibit estrogen stimulated proliferation in the endometrium. This action of antiprogestins would be of benefit to women treated with estrogen replacement therapy as a method of blocking untoward effects of estrogen on the endometrium. ZK 230 211 (ZK211) is a potent new generation antiprogestin produced by Schering AG, that can be administered both orally and systemically. The goal of this research was to determine if ZK211 will inhibit the proliferative actions of estrogen delivered continuously for 5 months. Six groups of rhesus macaques (n = 5 each) were treated with estradiol (E2)-filled implants for 5 months. Three of the groups were also injected daily with 3 different doses of ZK211 (0. 01, 0.05 and 0.25 mg/kg). P is known to oppose the proliferative action of E2 in the endometrium. Therefore, for comparison, 1 group received E2 plus a low dose of P (2 cm P implants) and one group received E2 plus a high dose of P (6 cm P implants). Control animals (group 6) received estrogen alone. Treatment with ZK211 resulted in a severe reduction of endometrial mass, which was associated with a dose dependent inhibition of epithelial cell proliferation. At higher doses of ZK211, this effect resulted in the upper portions of the glands degenerating and trapping secretory material. These higher doses led to formation of moderate size endometrial cysts, which appeared to contain trapped secretory material. There was no evidence of endometrial hyperplasia or metaplasia. As anticipated, long-term E2 + P treatment resulted in a dose-dependent decidualization response that was marked by extensive spiral artery hypertrophy. This effect on the spiral arteries was opposite to the reaction to that seen with ZK 211 which inhibited vascular development. We conclude that inhibition of vascular development by ZK 211 may be the key factor underlying the degenerative inhibition and blockade of estrogen-dependent endometrial proliferation induced by this antiprogestin. FUNDING Contract with Schering AG, Berlin, Germany PUBLICATIONS None